Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , acts as a bronchoconstrictor
and may cause severe bronchospasm. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) is
for diagnostic purposes only. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) should
only be conducted by trained professionals under the supervision of a physician
familiar with all aspects of the bronchial challenge test and the management
of acute bronchospasm. Medications (such as short acting inhaled beta-agonist)
and equipment to treat severe bronchospasm must be present in the testing area.
If severe bronchospasm occurs it should be treated immediately by administration
of a short acting inhaled beta-agonist. Because of the potential for severe
bronchoconstriction, the bronchial challenge testing with ARIDOL (mannitol inhalation powder) should not
be performed in any patient with clinically apparent asthma or very low baseline
pulmonary function tests (e.g., FEV1 < 1-1.5 liters or < 70%
of the predicted values) [see WARNINGS AND PRECAUTIONS].

DESCRIPTION

D-mannitol (referred to throughout as mannitol), the active ingredient in ARIDOL (mannitol inhalation powder)
is a hexahydric alcohol, that is a sugar alcohol, with the following chemical
name (2R,3R,4R,5R)-hexane-1,2,3,4,5,6­hexol and chemical structure:

Mannitol is a white or almost white crystalline powder of free-flowing granules
with an empirical formula of C6H14O6 and molecular
weight of 182.2. Mannitol is freely soluble in water, and very slightly soluble
in alcohol. Mannitol shows polymorphism.

The ARIDOL (mannitol inhalation powder) bronchial challenge test kit contains one single patient use dry
powder inhaler and 3 consecutively numbered foil blister packs containing a
total of 19 capsules of mannitol for oral inhalation. All except the 0 mg printed
hard gelatin capsules contain dry powder mannitol for oral inhalation. The accompanying
dry powder inhaler is a plastic device used for inhaling the capsules. All doses
are to be administered using the same device supplied with each kit without
washing or sterilizing the device at anytime during the test.

To use the delivery system, a mannitol capsule is placed in the well of the
inhaler, and the capsule is pierced by pressing and releasing the buttons on
the side of the device. The mannitol dry powder is dispersed into the air stream
when the patient inhales rapidly and deeply through the mouthpiece.

There are no inactive ingredients in the mannitol capsules supplied with the
ARIDOL (mannitol inhalation powder) bronchial challenge test kit. The 0 mg capsule and the bodies of the
5, 10, 20 and 40 mg capsules are clear. The white caps (5 mg) contain titanium
dioxide. The yellow caps (10 mg) contain titanium dioxide and yellow iron oxide.
The pink caps (20 mg) and red caps (40 mg) contain titanium dioxide and red
iron dioxide. The inhaler is a plastic device used for administering mannitol
to the lungs. The amount of drug delivered to the lung will depend on patient
factors, such as inspiratory flow rate and inspiratory time. Under standardized
in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the
delivered dose from the inhaler from each of the 5, 10, 20 and 40 mg capsules
is approximately 3.4, 7.7, 16.5 and 34.1 mg, respectively. Peak inspiratory
flow rates (PIFR) achievable through the inhaler were evaluated in healthy and
asthmatic individuals ranging from 7 to 65 years of age and with % FEV1
of predicted ranging from 67% to 123%. PIFR achieved in the study was at least
70.8 L/min in all subjects assessed. The mean PIFR was 118.2 L/min and approximately
ninety percent of each population studied generated a PIFR through the device
exceeding 90 L/min.

Indications & Dosage

INDICATIONS

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , is a sugar alcohol indicated for
the assessment of bronchial hyperresponsiveness in patients 6 years of age or
older who do not have clinically apparent asthma.

Limitations of Use

ARIDOL (mannitol inhalation powder) is not a stand alone test or a screening test for asthma. Bronchial
challenge testing with ARIDOL (mannitol inhalation powder) should be used only as part of a physician's

DOSAGE AND ADMINISTRATION

Basic Dosing Information

ARIDOL is a test kit containing the required capsules of dry powder mannitol
for oral inhalation in graduated doses with the supplied single patient use
inhaler necessary to perform one bronchial challenge test. The inhaler should
be discarded after use.

Do not swallow ARIDOL (mannitol inhalation powder) capsules.

The airway response to bronchial challenge testing with ARIDOL (mannitol inhalation powder) is measured
using forced expiratory volume in one second (FEV1).

Prior to bronchial challenge testing with ARIDOL (mannitol inhalation powder) , standard spirometry should
be performed and the reproducibility of the resting FEV1 established.

An overview of the testing procedure can be found below. See the ARIDOL (mannitol inhalation powder) bronchial
challenge test instructions for complete instructions on the dosing and spirometry
procedures.

A nose clip may be used if preferred. If so, apply nose clip to the subject
and direct the subject to breathe through the mouth

Insert 0 mg capsule into inhalation device. Puncture capsule by depressing
buttons on side of device slowly, and once only (a second puncture may fragment
the capsules)

The patient should exhale completely, before inhaling from device in a controlled
rapid deep inspiration

At the end of deep inspiration, start 60 second timer, subject should hold
breath for 5 seconds and exhale through mouth before removal of nose clip

At the end of 60 seconds, measure the FEV1 in duplicate (the
measurement after inhaling the 0 mg capsule is the baseline FEV1)

Repeat steps a-e following the mannitol capsule dose steps from Table 1
below until the patient has a positive response or 635 mg of mannitol has
been administered (negative test)

A positive response is achieved when the patient experiences a 15% reduction
in FEV1 from (0 mg) baseline (or a 10% incremental reduction in FEV1
between consecutive doses). The test result is expressed as a PD15.

Patients with either a positive response to bronchial challenge testing with
ARIDOL (mannitol inhalation powder) or significant respiratory symptoms should receive a standard dose of
a short acting inhaled beta-agonist and monitored until fully recovered to within
baseline.

The ARIDOL (mannitol inhalation powder) bronchial challenge test should only be used with the provided inhaler.
All remaining unused (opened and unopened) blister packs and the inhaler should
be properly discarded at the completion of the test. Be sure to read the accompanying
ARIDOL (mannitol inhalation powder) bronchial challenge test kit instructions completely before test initiation.
If you have any questions, contact the manufacturer support at 1-888-659-6396.

SIDE EFFECTS

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , is a sugar alcohol that may cause
severe bronchospasm in susceptible subjects [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect
the rates observed in practice.

The safety population for the ARIDOL (mannitol inhalation powder) bronchial challenge test consisted of
1,082 subjects (577 females and 505 males) including patients with asthma, symptoms
suggestive of asthma, and healthy individuals from 6 to 83 years of age who
participated in the two clinical trials (Studies 1 and 2). The racial distribution
of subjects was 84% Caucasian, 5 % Asian, 4 % Black, and 7 % Other. Children
and adolescents comprised 23% of the total study population with 118 children
aged 6-11 years and 128 adolescents aged 12-17 years.

Adverse reactions were reported at the time of the testing procedure and for
one day thereafter. No serious adverse reactions were reported following bronchial
challenge testing with ARIDOL (mannitol inhalation powder) in either trial.

Five adult subjects (0.6%) discontinued from the studies within a day following
bronchial challenge testing with ARIDOL (mannitol inhalation powder) because of cough, decreased lung function,
feeling jittery, sore throat, and throat irritation. One adult subject (0.3%)
discontinued following the methacholine bronchial challenge test because of dizziness. One pediatric subject (0.4%) discontinued from the studies within
a day following bronchial challenge testing with ARIDOL (mannitol inhalation powder) because of retching.

Table 2 displays the combined common adverse reactions ( ≥ 1%) within a day
after bronchial challenge testing with ARIDOL (mannitol inhalation powder) or methacholine in the overall
population for Studies 1 and 2.

Table 2: Adverse reactions with an incidence ≥ 1% within
a day after bronchial challenge testing (overall population, Studies 1 and 2
combined)

Adverse Reactions

Treatment

ARIDOL (mannitol inhalation powder)
(N=1046)
n (%)

Methacholine Challenge
(N=420)
n (%)

Headache

59 (6)

4 (1)

Pharyngolaryngeal pain

25 (2)

0

Throat irritation

19 (2)

1 ( < 1)

Nausea

19 (2)

0

Cough

17 (2)

8 (2)

Rhinorrhea

16 (2)

0

Dyspnea

15 (1)

21 (5)

Chest discomfort

13 (1)

18 (4)

Wheezing

8 (1)

6 (1)

Retching

6 (1)

0

Dizziness

5 (1)

13 (3)

The maximum reduction in FEV1 following bronchial challenge testing
with ARIDOL (mannitol inhalation powder) was 46%, compared to 54% for exercise testing and 67% for the methacholine
challenge. The incidences in decreases in FEV1 ≥ 30% and ≥ 60%
following ARIDOL (mannitol inhalation powder) , methacholine, and exercise challenges for Studies 1 and 2
is shown in Table 3.

There were no differences in the incidence of adverse reactions based on gender
or race. The clinical trials did not include sufficient numbers of subjects
65 years of age and older to determine whether they respond differently compared
to subjects below 65 years of age.

Children and Adolescent Aged 6 to 17 Years

Overall, the types and severities of adverse reactions in children were similar
to those observed in the adult population. As in the adult population, the
adverse reactions of pharyngolaryngeal pain, nausea, and headache were the more
common with incidences of 4%, 3%, and 3%, respectively. There were no major
differences in the types of adverse reactions observed in children 6-11 years
of age compared to adolescents 12-17 years old.

The decrease in FEV1 in children and adolescents who received the
ARIDOL (mannitol inhalation powder) bronchial challenge test was similar to that of the adult population
with 5%, 15% and 9% of pediatric subjects who had bronchial challenge testing
with ARIDOL (mannitol inhalation powder) , methacholine and exercise, respectively, experiencing reduction
in FEV1 ≥ 30%. No patient who had bronchial challenge testing with
ARIDOL (mannitol inhalation powder) or exercise had a decrease in FEV1 ≥ 60%, whereas, one
adolescent patient (aged 12 years) who received methacholine had a decrease
in FEV1 ≥ 60%.

Post-Marketing Experience

The following adverse reactions have been identified post approval outside
the U.S. of the ARIDOL (mannitol inhalation powder) bronchial challenge test kit: cough, gagging, wheeze,
and decreased forced expiratory volume. Because these reactions are reported
voluntarily from a population of uncertain size, it is not always possible
to reliably estimate their frequency or establish a causal relationship to drug
exposure.

DRUG INTERACTIONS

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Severe Bronchospasm

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , acts as a bronchoconstrictor and
may cause severe bronchospasm in susceptible patients. The test should only
be conducted by trained professionals under the supervision of a physician familiar
with all aspects of the bronchial challenge test and the management of acute
bronchospasm. Patients should not be left unattended during the bronchial challenge
test. Medications and equipment to treat severe bronchospasm must be present
in the testing area.

If a patient has a ≥ 10% reduction in FEV1 (from pre-challenge
FEV1) on administration of the 0 mg capsule, the ARIDOL (mannitol inhalation powder) bronchial
challenge test should be discontinued and the patient should be given a dose
of a short acting inhaled beta-agonist and monitored accordingly.

Patients with either a positive response to bronchial challenge testing with
ARIDOL (mannitol inhalation powder) or significant respiratory symptoms should receive a short acting inhaled
beta-agonist. Subjects should be monitored until fully recovered to within baseline.

Subjects with Co-morbid Conditions

Bronchial challenge testing with ARIDOL (mannitol inhalation powder) should be performed with caution in
patients with conditions that may increase sensitivity to the bronchoconstricting
or other potential effects of ARIDOL (mannitol inhalation powder) such as severe cough, ventilatory impairment,
spirometry-induced bronchoconstriction, hemoptysis of unknown origin, pneumothorax,
recent abdominal or thoracic surgery, recent intraocular surgery, unstable angina,
or active upper or lower respiratory tract infection.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies in rats and mice mannitol did not show evidence
of carcinogenicity at oral dietary concentrations up to 5% (or 7,500 mg/kg on
a mg/kg basis). These doses were approximately 55 and 30 times the MRHDID, respectively,
on a mg/m² basis.

The effect of inhaled mannitol on fertility has not been investigated.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled clinical studies
of mannitol in pregnant women. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) should
be performed during pregnancy only if the potential benefit justifies the potential
risk to the fetus.

Teratogenic Effects

Mannitol was not teratogenic. Mannitol did not
cause any embryofetal malformations when given to pregnant rats and mice at
oral doses approximately 20 and 10 times the maximum recommended human daily
inhalation dose (MRHDID) in adults, respectively, on a mg/m² basis [see
Animal Toxicology and/or Pharmacology].

Labor and Delivery

The effects of a possible hyperresponsiveness reaction on a mother or child
during labor or delivery are not known, and therefore bronchial challenge testing
with ARIDOL (mannitol inhalation powder) should not be administered during labor or delivery.

Nursing Mothers

It is not known whether mannitol is excreted in human milk. Because many drugs
are excreted in human milk, caution should be exercised when mannitol is given
to a nursing mother.

Pediatric Use

A total of 246 children and adolescents ages 6 to 17 years were studied in
the two clinical trials [see Clinical Studies].

The mean and median maximum percentage reduction in FEV1 in patients
with a positive ARIDOL (mannitol inhalation powder) challenge test in children and adolescents 6 to 17 years
of age (19% and 18%, respectively) showed no apparent difference compared to
the adult population (19% and 18%, respectively).

The safety profile of the ARIDOL (mannitol inhalation powder) bronchial challenge test in children and adolescents
6 to 17 years of age was similar to the adult population in two clinical studies
[see ADVERSE REACTIONS].

Bronchial challenge testing with ARIDOL (mannitol inhalation powder) should not be performed in children
less than 6 years of age due to their inability to provide reliable spirometric
measurements.

Geriatric Use

There was insufficient number of subjects 50 years of age and older in the
clinical program. Therefore, the safety and efficacy of bronchial challenge
testing with ARIDOL (mannitol inhalation powder) in the older population cannot be adequately assessed.
It is unknown whether any differences in the safety and efficacy of bronchial
challenge testing with ARIDOL (mannitol inhalation powder) exist between subjects 50 years of age and older
and younger subjects.

Hepatic and Renal Impairment

Formal pharmacokinetic studies with mannitol, the active ingredient, in ARIDOL (mannitol inhalation powder) ,
have not been conducted in patients with hepatic or renal impairment. However,
an increase in systemic exposure of mannitol can be expected in patients with
renal impairment based on the kidney being its primary route of elimination.

Given parenterally, mannitol is used as an osmotic diuretic in a variety of
clinical situations including acute renal failure where the osmotic effects
of mannitol inhibit the rate of water re-absorption and maintain the rate of urine production.

Overdosage & Contraindications

OVERDOSE

Mannitol, the active ingredient in ARIDOL (mannitol inhalation powder) , is to be administered only by inhalation.
Susceptible persons may experience excessive bronchospasm from an overdose.
If such bronchospasm occurs, immediately administer a short acting inhaled beta-agonist
and other medical treatments such as oxygen, as necessary.

CONTRAINDICATIONS

ARIDOL (mannitol inhalation powder) use is contraindicated in:

Patients with known hypersensitivity to mannitol or to the gelatin used
to make the capsules

CLINICAL PHARMACOLOGY

Mechanism of Action

The precise mechanisms through which inhaled mannitol causes bronchoconstriction
are not known.

Pharmacodynamics

The response to inhaled mannitol is reported as the delivered dose of mannitol
causing a 15% reduction in FEV1 and is expressed as PD15.

Pharmacokinetics

Absorption

The rate and extent of absorption of mannitol after oral inhalation was generally
similar to that observed after oral administration. In a study of 18 healthy
adult male subjects the absolute bioavailability of mannitol powder following
oral inhalation was 59% while the relative bioavailability of inhaled mannitol
in comparison to orally administered mannitol was 96%. Following oral inhalation
of 635 mg, the mean mannitol peak plasma concentration (Cmax) was 13.71 mcg/mL
while the mean extent of systemic exposure (AUC) was 73.15 mcg•hr/mL. The mean
time to peak plasma concentration (Tmax) after oral inhalation was 1.5 hour.

Distribution

Based on intravenous administration, the volume of distribution of mannitol
was 34.3 L.

Metabolism

The extent of metabolism of mannitol appears to be small. This is evident from
a urinary excretion of about 87% of unchanged drug after an intravenous dose
to healthy subjects.

Elimination

Following oral inhalation, the elimination half-life of mannitol was 4.7 hours.
The mean terminal elimination half-life for mannitol in plasma remained unchanged
regardless of the route of administration (oral, inhalation, and intravenous).
The urinary excretion rate versus time profile for mannitol was consistent for
all routes of administration. The total clearance after intravenous administration
was 5.1 L/hr while the renal clearance was 4.4 L/hr. Therefore, the clearance
of mannitol was predominately via the kidney. Following inhalation of 635 mg
of mannitol in 18 healthy subjects, about 55% of the total dose was excreted
in the urine as unchanged mannitol. Following oral or intravenous administration
of a 500 mg dose, the corresponding values were 54% and 87% of the dose, respectively.

Hepatic and Renal Impairment

Formal pharmacokinetic studies using ARIDOL (mannitol inhalation powder) have not been conducted in patients
with hepatic or renal impairment. Since the drug is eliminated primarily via
the kidney, an increase in systemic exposure can be expected in renally impaired
patients.

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Mannitol did not cause any embryofetal malformations when given to pregnant
rats and mice at oral doses of 1.6 g/kg each (approximately 20 and 10 times
the MRHDID in adults, respectively, on a mg/m² basis).

Clinical Studies

The effectiveness of the ARIDOL (mannitol inhalation powder) bronchial challenge test kit in assessing bronchial
hyperresponsiveness in adults and children 6 years of age and older was assessed
in two clinical studies. Study 1 was an operator-blinded, open-label crossover
trial that assessed the sensitivity and specificity of bronchial challenge testing
with ARIDOL (mannitol inhalation powder) compared with a methacholine bronchial challenge test in detecting
bronchial hyperresponsiveness in subjects with symptoms suggestive of asthma
but without a definite diagnosis of asthma. During the course of the study subjects
underwent three types of bronchial challenge tests utilizing exercise, ARIDOL (mannitol inhalation powder) ,
and methacholine. A positive exercise test was defined as a decrease in FEV1
≥ 10%, a positive bronchial challenge test with ARIDOL (mannitol inhalation powder) was defined by either
a decrease in FEV1 by ≥ 15% from baseline or a between-dose reduction
in FEV1 ≥ 10%, and a positive methacholine response was defined
as a decrease in FEV1 ≥ 20% after breathing methacholine at a
concentration less than or equal to 16 mg/mL. The sensitivity and specificity
of bronchial challenge testing with ARIDOL (mannitol inhalation powder) and methacholine were then assessed
relative to exercise testing which served as a common comparator. The sensitivity
and specificity of ARIDOL (mannitol inhalation powder) and methacholine challenges were also assessed using
a blinded study physician's diagnosis of asthma at the end of the study. Five-hundred
nine subjects aged 6 to 50 years were screened for enrolment with 419 and 420
subjects receiving at least one dose of mannitol, the active ingredient in ARIDOL,
or methacholine, respectively. The maximum cumulative dose of mannitol was 635
mg. Bronchial challenge testing with ARIDOL (mannitol inhalation powder) and methacholine demonstrated similar
sensitivity and specificity in predicting bronchial hyperresponsiveness defined
by a positive exercise challenge (Table 4).

Table 4 : Comparisons of the sensitivity and specificity
(calculated relative to exercise challenge) for the ARIDOL (mannitol inhalation powder) test and methacholine
in Study 1

Population

Treatment

Sensitivity % (95% CI)

Specificity % (95% CI)

Overall Population (n=419)

ARIDOL

58 (50, 65)

63 (57, 69)

Methacholine

53 (46, 51)

68 (62, 73)

Difference

5 (-4, 13)

-5 (-12, 3)

Age 6-11 years old (n=36)

ARIDOL

67 (47, 87)

47 (21, 72)

Methacholine

71 (52, 91)

33 (9, 57)

Difference

-5 (-29, 20)

17 (-29, 62)

Age 12-17 years old (n=70)

ARIDOL

55 (37, 72)

62 (46, 77)

Methacholine

65 (48, 81)

64 (49, 79)

Difference

-10 (32, 13)

-3 (-24, 19)

Bronchial challenge testing with ARIDOL (mannitol inhalation powder) and methacholine also demonstrated
similar sensitivity and specificity when calculated relative to a blinded study
physician's diagnosis of asthma in subjects at the end of the study.

The sensitivity and specificity of bronchial challenge testing with ARIDOL (mannitol inhalation powder)
in children and adolescents 6 to 17 years of age in Study 1 was similar to that
in the overall population (Table 4).

Study 2 was a crossover study comparing bronchial challenge testing with ARIDOL (mannitol inhalation powder)
to hypertonic (4.5%) saline in identifying bronchial hyperresponsiveness in
subjects 6 to 83 years of age with (n=551) and without (n=95) asthma. In this
study the efficacy endpoint of interest was an estimation of the sensitivity
and specificity of bronchial challenge testing with ARIDOL (mannitol inhalation powder) with respect to a
physician's clinical diagnosis of asthma. Following completion of the bronchial
challenge tests with ARIDOL (mannitol inhalation powder) and hypertonic saline, a respiratory physician assessed
the data and categorized the subjects as having or not having asthma. The sensitivity
of the ARIDOL (mannitol inhalation powder) bronchial challenge test in subjects with a physician diagnosis
of asthma was 58% [(54%, 62%, 95th CI)] compared to a sensitivity of the physician
diagnosis in the same population of 97% [(95%, 98%, 95th CI)]. The specificity
of the ARIDOL (mannitol inhalation powder) bronchial challenge test in subjects without asthma was 95% [(90%,
99%, 95th CI)] compared to the specificity of the physician diagnosis of 98%
[(95%, 100%, 95th CI)].

Medication Guide

PATIENT INFORMATION

Severe Bronchospasm

Prior to administration patients should be informed of the potential for bronchial
challenge testing with ARIDOL (mannitol inhalation powder) to cause severe bronchospasm and of the potential
symptoms they may experience.

Subjects with Certain Co-morbid Conditions

Bronchial challenge testing with ARIDOL (mannitol inhalation powder) should be performed with caution in
patients having severe cough, ventilatory impairment, spirometry-induced bronchoconstriction,
hemoptysis of unknown origin, pneumothorax, recent abdominal or thoracic surgery,
recent intraocular surgery, unstable angina, or active upper or lower respiratory
tract infection or other conditions that may worsen with the use of a bronchial
irritant.

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.